A. Field of the Invention
The present invention relates to the fields of molecular biology, pathology and genetics. More specifically, the invention relates to methods of predicting and diagnosing autoimmune disease based on the presence or absence of single nucleotide polymorphisms.
B. Related Art
Autoimmune diseases comprises a large number of widely varying illnesses. Their common feature is the existence of an immune response in the subject against one or more “self” antigens, including such wide ranging molecules as proteins, DNA and carbohydrates. These diseases can cause symptoms ranging from only mild discomfort to the patient, to complete debilitation and death. Most of autoimmune diseases remain very enigmatic, not only in their molecular basis and precipitating factors, but in their prediction, progression and treatment. As such, they continue to provide a considerable challenge to the healthcare industry.
Most genetic-based diseases do not generally have a simple, single genetic cause. Moreover, they are usually affected by environmental factors as well. The same can be said for autoimmune diseases, where defects in multiple genes often are involved. The situation is not aided by clinical diagnosis, since (a) familial autoimmune disease is often characterized by related individuals suffering from distinct autoimmune defects, and (b) the same autoimmune disease may manifest itself differently in different individuals at different times. Thus, one is left with a difficult, if not impossible, clinical diagnosis even when some genetic information is available. That is why researches continue to seek out better and more complete genetic bases for autoimmune diseases.
Systemic Lupus Erythematosus (SLE), like other autoimmune diseases, is mediated by a complex interaction of genetic and environmental elements. The genetic component of this interaction is clearly important: 20% of people with SLE have a relative who has or will have SLE. It is commonly believed that environmental factors may trigger a genetic predisposition to such diseases. Although the crucial role of genetic predisposition in susceptibility to SLE has been known for decades, only minimal progress has been made towards elucidating the specific genes involved in human disease. It is also suspected that SLE may be related to genetic defects in apoptosis. For example, mice lacking the gene for DNase1 develop SLE by 6 to 8 months of age.
Family studies have identified a number of genetic regions associated with elevated risk for SLE, although no specific genes have yet been identified. Harley et al. (1998); Wakeland et al. (2001). For example, 1q42 has been linked to SLE in three independent studies. Reviewed in Gaffney et al. (1998). Other genetic locations revealed by model-based linkage analysis include 1q23 and 11q14 in African Americans, 14q11, 4p15, 11q25, 2q32, 19q13, 6q26-27, and 12p12-11 in European Americans, with 1q23, 13q32, 20q13, and 1q31 showing up in combined pedigrees. Moser et al. (1998). Associations have also been shown for the genetic markers HLA-DR2 and HLA-DR3. Arnett et al. (1992). More recently, expression profiling of peripheral blood mononuclear cells of SLE patients using microarrays has shown that about half of the patients demonstrate disregulated expression of genes in the IFN pathway. Baechler et al. (2003).
Despite these important observations, it is far from clear that one can predict the existence or predisposition to SLE based on this handful of genetic information. In all likelihood, a much more robust analysis using more and better genetic markers to identify SLE (and distinguish it from other autoimmune diseases) will be required.